6-51830849-A-T

Variant names:

• chr6-51830849-A-T
• rs1571084
• NM_138694.4:c.8302+12T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.8302+12T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,609,244 control chromosomes in the GnomAD database, including 143,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16090 hom., cov: 32)
  • Exomes 𝑓: 0.41 (127005 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.317
• Publications: 12 publications found

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-51830849-A-T is Benign according to our data. Variant chr6-51830849-A-T is described in ClinVar as Benign. ClinVar VariationId is 96429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.8302+12T>A		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.8302+12T>A		intron	N/A	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.8302+12T>A		intron	N/A	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.8302+12T>A		intron	N/A	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67445 AN: 151822 Hom.: 16065 Cov.: 32

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.0830

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.479

GnomAD2 exomes AF: 0.375 AC: 94101 AN: 250980 AF XY: 0.378

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.0823

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.440

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.409 AC: 596261 AN: 1457304 Hom.: 127005 Cov.: 31 AF XY: 0.407 AC XY: 294944 AN XY: 725232

African (AFR) AF: 0.600 AC: 20012 AN: 33326

American (AMR) AF: 0.250 AC: 11142 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 14406 AN: 26050

East Asian (EAS) AF: 0.0849 AC: 3365 AN: 39628

South Asian (SAS) AF: 0.312 AC: 26928 AN: 86192

European-Finnish (FIN) AF: 0.350 AC: 18653 AN: 53358

Middle Eastern (MID) AF: 0.534 AC: 3073 AN: 5750

European-Non Finnish (NFE) AF: 0.427 AC: 473386 AN: 1108194

Other (OTH) AF: 0.420 AC: 25296 AN: 60172

GnomAD4 genome AF: 0.444 AC: 67518 AN: 151940 Hom.: 16090 Cov.: 32 AF XY: 0.434 AC XY: 32257 AN XY: 74248

African (AFR) AF: 0.587 AC: 24338 AN: 41458

American (AMR) AF: 0.337 AC: 5141 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1949 AN: 3464

East Asian (EAS) AF: 0.0829 AC: 429 AN: 5178

South Asian (SAS) AF: 0.295 AC: 1421 AN: 4818

European-Finnish (FIN) AF: 0.344 AC: 3621 AN: 10526

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 28975 AN: 67928

Other (OTH) AF: 0.477 AC: 1008 AN: 2114

Alfa AF: 0.443 Hom.: 2885

Bravo AF: 0.456

Asia WGS AF: 0.259 AC: 901 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease 4 (2)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.89
DANN	Benign	0.45
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1571084; hg19: chr6-51695647; COSMIC: COSV61861095;